An important discovery using genetically altered mice has brought researchers one step closer to unraveling the mechanisms of nicotine addiction and even closer to the development of an effective treatment for one of the Nation's deadliest and most costly health problems--nicotine addiction.

Building on a series of recent scientific findings suggesting that, independent of a drug's initial site of action, every drug of abuse--be it nicotine, alcohol, heroin, cocaine, or amphetamine--appears to increase the levels of the neurotransmitter dopamine in a particular brain pathway, scientists may now have found a molecular link between nicotine addiction and this common reward or pleasure producing pathway.

Using sophisticated bioengineering tools, Marina Picciotto, Ph.D., Assistant Professor of Psychiatry at Yale Medical School, and colleagues at the Pasteur Institute in Paris, the Karolinska Institute in Stockholm, and the research section of Glaxo-Wellcome in Geneva, have pinpointed a particular molecule, the beta 2 subunit of a known nicotine receptor, as being essential to the process of nicotine addiction. This important molecular finding identifies the beta 2 subunit as a critical component in nicotine addiction, as well as a potential site for targeting the development of anti-nicotine addiction medications.

Picciotto and her colleagues used a strain of mice in which one of the 10 subunits, or molecules, that make up the neuronal nicotinic acetylcholine receptor was disabled or "knocked out." The most significant finding is that the mice lacking the b2 molecule failed to self-administer nicotine, implying that without this molecule, the mice do not experience the positive reinforcing properties of nicotine. Importantly, both the normal and the altered mice did self-administer cocaine. This all indicates that even without this b2 nicotine receptor molecule, the brain reward pathway thought to be common to all addictions remains intact even though nicotine loses its effect.

An important related finding is that an injection of nicotine given to the knockout mice did not increase the neurotransmitter dopamine. "We knew that dopamine was somehow involved in mediating the rewarding properties of nicotine addiction," said Dr. Alan I . Leshner, Director of NIDA, "but to actually pinpoint a particular molecule critical in this phenomenon is a major discovery. This finding will help us to more systematically develop medications for nicotine addiction targeted at these kinds of brain mechanisms."

"The fact that the researchers obtained different results between the knockout mice and the controls when they compared two different classes of abused drugs using a complex behavioral model like self-administration is what makes this study so innovative and unique," said Dr. Leshner. "It is this kind of a multi-disciplinary approach that combines behavioral and genetic engineering techniques that will enable us to unravel the remaining mysteries of addiction."

The findings from this research, which was supported in part by NIDA, can be found in the January 8, 1998, issue of Nature.

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